Stony Brook University, School of Health Technology and Management -- HAD 432

Adverse

drug reactions Adverse effects Drug interactions Idiosyncratic reactions Drug allergies

 Any

response to a drug that is noxious, unintended, and occurs at doses normally used in humans for the prophylaxis, diagnosis, or therapy of disease (WHO, 1984).

 Discontinue

the drug Modify the dose Hospitalize the patient Provide supportive measures

Effects of one drug can alter the effects of another drug Can increase or decrease the effect of the drug Both drugs effects can be altered, resulting in an ADR or a benefit

Duplication, ie. OTC cold remedy/sleep aid (diphenhydramine) and cold remedy with pain reliever (acetominophen) Opposition (antagonism)- reduce effect of one or both, ie. Ibuprofen relieves pain and retains salt, fluid, and NSAIDs reduce the effects of diuretics Alteration- affects how body absorbs, distributes, metabolizes, or excretes a drug, ie. Proton pump inhibitor can reduce stomach acid and decrease absorption of the antifungal drug ketoconazole

 Interaction

with food

Tetracycline-no milk or other dairy- calcium reduces drug absorption Grapefruit juice- inhibits the enzymes involved in metabolism of certain benzodiazepines, estrogens, or statins, intensifying their effects

Beneficial

interaction- pharmacodynamic synergy between diuretics and angiotensinconverting enzyme (ACE) inhibitors in the treatment of hypertension

 Unique,

strange, or unpredicted reaction to a

drug Caused by underlying enzyme deficiencies resulting from genetic or hormonal variation Example- transient quadriplegia, dizziness, temporary vision loss from the drug carisoprodol (Soma)

 Abnormal

response characterized by:

Occurrence in a small # of individuals Previous exposure to either the same or a chemically related drug Rapid development of an allergic reaction after re-exposure Production of clinical manifestations of an allergic reaction

 Difficult

to establish (no reliable lab tests) Symptoms can imitate infectious disease symptoms Is it a true allergic reaction or drug intolerance?

 An

idiosyncratic, sudden, and severe allergic reaction May be life threatening Can cause a sharp loss of blood pressure, urticaria, paralysis of the diaphragm, swelling of the oropharynx A true medical emergency, could cause cardiac collapse

Development of resistance to the effects of a drug Drugs doses must be continually raised to elicit the desired response Experienced with opiates, nitrates, barbiturates, alcohol, tobacco (DOA) Cross-tolerance: development of a resistance to chemically similar drugs Cumulative Effect: drug does not break down and starts to collect in the blood and body tissues Synergism: combined action of two or more drugs that produces an effect greater than that which would have been expected from the two agents acting separately, can be beneficial or harmful

 Defined

as an immune mediated response to a drug agent in a sensitized patient Drug allergy is defined as a reaction mediated by IgE Identifiable risk factors for drug hypersensitivity include:

Age Gender (female more common) Concurrent illness Previous hypersensitivity to related drugs Route of administration Chemical properties and mw of drug

 Non-Immunologic

Immunologic

75-80% of ADRs caused by predictable, nonimmunologic effects

5-10%

of drug reactions (true drug hypersensitivity)

*Remaining percent: ADR caused by unpredictable effects, may or may not be immunologic

Drug Reactions

 Mechanism-

Drug-IgE complex binds to mast cells with release of histamine, inflammatory mediators Clinical manifestations- angioedema, bronchospasm, pruritus, vomiting, diarrhea, anaphylaxis Timing of Reactions- minutes to hours after drug exposure

 Confirm

by detecting antigen-specific IgE by skin testing. If positive, discontinue drug. Negative skin test ok for penicillin, but does not rule out the presence of specific IgE. RAST (radioallergosorbent test)- less sensitive than skin. If + consider epinephrine, antihistamines, systemic corticosteroids, bronchodilators. Serum tryptase- peaks 1 hr after anaphylaxis, elevated 2-4 hrs after event. Inpatient monitoring ,if severe.

 Mechanism-

specific IgG or IgM antibodies directed at drug-hapten coated cells Clinical manifestations- hemolytic anemia, neutropenia, thrombocytopenia Timing of reactions- variable

 Complete

blood count Direct and/or indirect Coombs Test (reflects presence of complement and/or drug-hapten on red cell membrane)- positive result can confirm hemolytic anemia. Therapy- discontinue drug, consider systemic corticosteroids, transfusion in severe cases

 Mechanism-

tissue deposition of drugantibody complexes with complement activation and inflammation Clinical manifestations- serum sickness, fever, rash, arthralgias, lymphadenopathy, urticaria, glomerulonephritis, vasculitis Timing of reactions- 1 to 3 weeks after drug exposure

 ESR-

increased, discontinue drug C-reactive protein- positive, consider NSAIDs, antihistamines, or systemic corticosteroids. Immune complexes Antinuclear antibody, antihistone antibody Tissue biopsy for immunofluorescence studies

 Mechanism-

MHC presents drug molecules to T cells with cytokine and inflammatory mediator release Clinical manifestations- allergic contact dermatitis, maculopapular drug rash Timing of reactions- 2 to 7 days after cutaneous drug exposure

 Patch

testing- positive, discontinue use Lymphocyte proliferation assay(investigational test)- positive, consider topical corticosteroids, antihistamines, or systemic corticosteroids if severe

 Cross

reactivity between a beta-lactam ring and penicillin Do not use carbapenems in patients allergic to penicillin Cross reactivity with cephalosporins and penicillins documented, low incidence, but could be anaphylaxis (fatal) Need to know if patient is allergic to radiocontrast medias (pretreatment protocols if necessary)